Optogenetic Tool Controls Voltage-Gated Calcium Channels

An optogenetic tool has been developed for controlling voltage-gated calcium (Ca_V) channels to enable photo-tunable modulation of Ca_V channel activity in excitable mammalian cells. The tool, called optoRGK, provides a way to interrogate the physiological and pathophysiological processes that are mediated by Ca_V channels.

Voltage-gated Ca²⁺ channels (Ca_V) are important therapeutic targets for cardiovascular and neuropsychiatric disorders. Researchers engineered a class of genetically encoded photoswitchable inhibitors for Ca_V channels to control Ca²⁺ signals (yellow graphs in round bubbles) and biological activities in excitable cells. This optogenetic device, optoRGK, can be adapted to suppress cardiac arrhythmia (asterisks), thereby intervening in atrial fibrillation and other cardiovascular disorders by light. Courtesy of Yubin Zhou, Texas A&M University Health Science Center.

Ca_V channels constitute the major route of calcium entry into the cell and regulate a series of physiological processes. Traditional calcium-channel blockers, widely used to treat cardiovascular disorders, can cause cytotoxicity and off-target effects.

Researchers at Texas A&M University combined genetic strategies with optical techniques to engineer a new class of genetically encoded inhibitors for Ca_V channels. The team tested this photoswitchable inhibitor in cardiac muscle cells. In the dark, the muscle cells showed rhythmic oscillations of calcium that matched the heart beating rhythm.

“However, upon blue light illumination, the rhythmic oscillations can be substantially reduced or even terminated. Notably, this process is totally reversible after removal of the light source,” said professor Yubin Zhou.

Using this method, researchers can regulate the activity of excitable cells in the nervous and cardiovascular systems.

“The optoRGK toolkit provides a unique opportunity to switch off calcium signals in excitable cells,” said researcher Youjun Wang from Beijing Normal University.

Although it is tailored for Ca_V channels, optoRGK could find broad applications in interrogating a wide range of Ca_V-mediated physiological processes.

“Our optogenetic tools can be conveniently applied to control a wide range of physiological processes mediated by voltage-gated calcium channels in multiple biological systems. While traditional voltage-gated calcium- channel blockers lack reversibility, selectivity, and tissue-specificity, optoRGK opens exciting opportunities to intervene in related physiological processes with unprecedented precision. We hope that these kinds of studies will eventually lead to a new generation of optogenetic devices for curing cancer, and cardiovascular and neurological diseases,” said Zhou.

The research was published in Angewandte Chemie (doi:10.1002/anie.201713080).